Inherited peripheral neuropathy (IPN) is a genetically and clinically heterogeneous group of disorders encompassing Charcot Marie Tooth disease (CMT; also termed hereditary motor and sensory neuropathy, HMSN), hereditary neuropathy with liability to pressure palsy (HNPP), hereditary motor neuropathy (HMN), and hereditary sensory and autonomic neuropathy (HSAN). Among these, the CMT is the most commonly occurring IPN with a frequency of 1 in 2,500 people. The characteristic clinical features of CMT are symmetrical distal polyneuropathy, such as distal wasting, weakness, foot deformities, and slowly-progressing sensory loss in the lower limbs.
More than 80 relevant genes causing CMT have been isolated. Among these, the most frequent CMT-causative genes include peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ), gap junction protein beta 1 (GJB1), and mitofusin 2 (MFN2), which account for approximately 90% of the CMT cases. These genes cause disease in an autosomal dominant or X-linked dominant manner. Over 95% of the CMT cases are dominantly inherited, whereas very few cases are inherited in an autosomal recessive or X-linked recessive manner. Although the majority of the autosomal dominant cases are caused by duplication of a PMP22 gene, more than 50% of the cases are caused by point mutations in 40 or more genes.
Clinically applicable methods of treating genetically recessive diseases include gene therapy, enzyme replacement, and cell transplantation. However, these clinical approaches are limited in autosomal dominant cases, which are caused by gain-of-function mutations of mutant proteins. Although various strategies have been proposed to bypass the detrimental effect of the mutant proteins, fundamental therapeutic methods should be based on the suppression or the removal of mutant alleles or proteins.
Meanwhile, as small interfering RNA (siRNA) targets a specific sequence of a gene, modulating the specificity of siRNA to the mutant alleles is considered to be theoretically feasible gene therapy. Indeed, it was reported that, when mutant allele-specific short hairpin RNA (shRNA) is administered via a viral delivery system, the mutant allele-specific shRNA has a therapeutic effect on various disease models including Alzheimer's disease, Parkinson's disease, Huntington's disease, Machado-Joseph disease, and amyotrophic lateral sclerosis.